Wnt proteins comprise a large family of structurally related, extracellular agents that have a variety of important functions during embryonic development (Cadigan and Nusse, Genes Dev. 11:3286–3305, 1997 and Dale, T. C., Biochem J. 329:209–223, 1998). They specify cell polarity and fate, stimulate proliferation, and contribute to the patterning of tissue in many animal models. Wnt signaling also has been strongly implicated in the development of neoplasia.
A set of secreted Fz-related proteins (sFRP or FRP) recently have been described (Leyns et al., Cell 88:747–756, 1997; Wang et al., Cell 88:757–766,1997; Rattner et al., Proc. Natl. Acad. Sci. U.S.A. 94:2859–2863, 1997; Finch et al., Proc. Natl. Acad. Sci. U.S.A. 94:6770–6775, 1997; Salic et al., Development 124:4739–4748, 1997; Melkonyan et al., Proc. Natl. Acad. Sci. U.S.A. 94:13636–13641, 1997; Pfeffer et al., Intl. J. Dev. Biol. 41:449–458, 1997; Mayr et al., Mech. Dev. 63:109–125,1997; Wolf et al., FEBS Lett. 417:385–389, 1997; Xu et al., Development 125:4767–4776, 1998; Chang et al., Hum. Mol. Genet. 8:575–583, 1999; and Abu-Jawdeh et al., Lab. Invest. 79:439–447, 1999). These proteins consist ofapproximately 300 amino acids. including a CRD (cysteine rich domain) that is typically 30–50% identical to the CRDs of Fz family members. The carboxyl-terminal portion of these proteins often contains segments rich in positively charged residues, and two (sFRP-1 and FrzB/sFRP-3) were reported to bind tightly to heparin (Finch et al. Proc. Natl. Acad Sci. U.S.A. 94:6770–6775, 1997 and Hoang et al. J. Biol. Chem. 271:26131–26137, 1996). The CRD has been also found to be the Wnt binding site based on several experiments in which the Fz CRD conferred Wnt binding and/or responsiveness (Hsieh et al., Proc. Natl. Acad. Sci. U.S.A. 96:3546–3551, 1999; Bhanot et al., Nature 382:225–230, 1996; and He et al., Science 275:1652–1654, 1997).